The prefrontal cortex (PFC) guides complex behaviors such as working memory and future planning, and disruption of the cortical dopamine (DA) innervation in animals causes behavior consistent with PFC damage. Furthermore, schizophrenic patients exhibit behavioral deficits resembling PFC dysfunction, as well as morphological abnormalities and reduced DA innervation in the postmortem PFC. These observations suggest that an intact mesocortical DA innervation is essential for proper functioning of the PFC. However, the cellular mechanisms underlying DA's crucial modulation are not known. To understand these mechanisms, the synaptic organization of the mesocortical DA pathway must be clearly delineated. In the PFC of rodents and primates, DA terminals synapse on the dendritic spines and/or shafts of glutamate pyramidal neurons and GABA local circuit neurons; in both cases they converge with excitatory, presumed glutamate afferents. However, there remain several critical questions regarding this synaptic organization that can be addressed using a combined immunocytochemical, tract-tracing, and electron microscopic approach in the rat PFC. The central hypothesis of these studies is that DA terminals do not associate uniformly with all cell types, afferents, and cellular compartments. Study Q 1.1 will identify the subclasses of GABA local circuit neurons, defined by their content of calcium-binding proteins, that are synaptically innervated by DA terminals. Study Q1.2 will identify the sources of excitatory glutamate afferents that target the local circuit neurons receiving DA input. Study Q2.1 will identify the populations of PFC pyramidal neurons, deemed by their principal axon projections, that are synaptically innervated by DA terminals. Study Q2.2 will identify the sources of excitatory glutamate afferents that converge synaptically with DA terminals on common pyramidal cell dendrites. Study Q3.1 will identify differences in the distribution of DA terminal synapses on the apical and basilar tuft dendrites of individual pyramidal neurons. The latter study will be performed on neurons recorded intracellularly in vitro, thus permitting correlation of anatomical data with physiological and pharmacological experiments funded independently. These comparative studies will provide valuable information regarding extrapolation to humans of anatomical, physiological, and neurochemical data collected in experimental animals. Elucidating the synaptic organization of the mesocortical DA system will improve knowledge of the cellular mechanisms of DA modulation in cognition and the pathophysiology and treatment of major psychiatric disorders.